Utility of Epstein-Barr Virus DNA in Nasopharynx Swabs as a Reflex Test to Triage Seropositive Individuals in Nasopharyngeal Carcinoma Screening Programs.

BACKGROUND: Epstein-Barr virus (EBV) DNA detection in the nasopharynx is considered a biomarker for nasopharyngeal carcinoma (NPC). We evaluated its performance as a reflex test to triage EBV seropositives within an NPC screening program in China. METHODS: The study population was embedded within an ongoing NPC screening trial and included 1111 participants who screened positive for anti-EBV VCA (antibodies against EBV capsid antigens)/EBNA1 (EBV nuclear antigen1)-IgA antibodies (of 18 237 screened). Nasopharynx swabs were collected/tested for EBNA1 gene EBV DNA load. We evaluated performance of EBV DNA in the nasopharynx swab as a reflex test to triage EBV serological high-risk (those referred to endoscopy/MRI) and medium-risk (those referred to accelerated screening) individuals. RESULTS: By the end of 2019, we detected 20 NPC cases from 317 serological high-risk individuals and 4 NPC cases from 794 medium-risk individuals. When used to triage serological high-risk individuals, nasopharynx swab EBV DNA was detected in 19/20 cases (positivity rate among cases: 95.0%; 95% CI, 75.1%-99.9%), with a referral rate of 63.4% (201/317, 95% CI, 57.8%-68.7%) and NPC detection rate among positives of 9.5% (19/201, 95% CI, 5.8%-14.4%). The performance of an algorithm that combined serology with triage of serology high-risk individuals using EBV DNA testing yielded a sensitivity of 72.4% (95% CI, 3.0%-81.4%) and specificity of 97.6% (95% CI, 97.2%-97.9%). When used to triage EBV serological medium-risk individuals, the positivity rate among cases was 75.0% (95% CI, 19.4%-99.4%), with a referral rate of 61.8% (95% CI, 58.4%-65.2%) and NPC detection rate among positives of 0.6% (95% CI, 0.1%-1.8%). CONCLUSIONS: Nasopharynx swab EBV DNA showed promise as a reflex test to triage serology high-risk individuals, reducing referral by ca. 40% with little reduction in sensitivity compared to a serology-only screening program.

Trends of outcomes and healthcare utilization following orthopaedic procedures in adults with haemophilia: A 3-decade retrospective review.

INTRODUCTION: Haemophilic arthropathy is a serious complication of haemophilia often requiring surgical intervention. It is unclear whether advances in comprehensive care are associated with a reduction in orthopaedic interventions and peri-procedural resource utilization. AIM: To determine temporal patterns of orthopaedic interventions in persons with haemophilia (PWH), and evaluate changes in healthcare utilization and outcomes. METHODS: In this Canadian multicentre retrospective cohort study, adult PWH from Northern Alberta and British Columbia who underwent orthopaedic procedures (1990-2018) were included. Temporal changes in the type of procedures, length of stay (LOS), factor utilization and outcomes were examined. RESULTS: Sixty-five patients (78% haemophilia A) underwent 102 surgeries at a median age of 46.3. Of the 46 severe PWH, 28 (61%) were on prophylaxis at time of surgery. The proportion of total knee arthroplasties (TKA) declined over time (56% 1990-1999, 51% 2000-2009, 27% 2010-2018), with a concomitant rise in ankle arthrodesis (0% 1990-1999, 18% 2000-2009, 27% 2010-2018). Over time, PWH underwent orthopaedic procedures at an older age (P = .02). There was a significant reduction in perioperative factor VIII utilization (P = .003) and median LOS (P < .0001). Major bleeds, prosthetic joint infections and thrombosis were not observed in the last decade. CONCLUSION: In the last three decades, there was a decline in the proportion of TKA, likely reflecting the impact of widespread use of tertiary prophylaxis. However, ankle arthrodesis rates increased, suggesting that higher trough levels may be required to prevent ankle arthropathy. We observed a significant reduction in LOS and factor utilization, reflecting improvements in perioperative management.

Prospective assessment of a nasopharyngeal carcinoma risk score in a population undergoing screening.

Despite evidence suggesting the utility of Epstein-Barr virus (EBV) markers to stratify individuals with respect to nasopharyngeal carcinoma (NPC) risk in NPC high-risk regions, no validated NPC risk prediction model exists. We aimed to validate an EBV-based NPC risk score in an endemic population undergoing screening for NPC. This prospective study was embedded within an ongoing NPC screening trial in southern China initiated in 2008, with 51 235 adult participants. We assessed the score's discriminatory ability (area under the receiver-operator-characteristics curve, AUC). A new model incorporating the EBV score, sex and family history was developed using logistic regression and internally validated using cross-validation. AUCs were compared. We also calculated absolute NPC risk combining the risk score with population incidence and competing mortality data. A total of 151 NPC cases were detected in 2008 to 2016. The EBV-based score was highly discriminating, with AUC = 0.95 (95% CI = 0.93-0.97). For 90% specificity, the score had 87.4% sensitivity (95% CI = 81.0-92.3%). As specificity increased from 90% to 99%, the positive predictive value increased from 2.4% (95% CI = 1.9-3.0%) to 12.5% (9.9-15.5%). Correspondingly, the number of positive tests per detected NPC case decreased from 272 (95% CI = 255-290) to 50 (41-59). Combining the score with other risk factors (sex, first-degree family history of NPC) did not improve AUC. Men aged 55 to 59 years with the highest risk profile had the highest 5-year absolute NPC risk of 6.5%. We externally validated the discriminatory accuracy of a previously developed EBV score in a high-risk population. Adding nonviral risk factors did not improve NPC prediction.

College of American Pathologists Tumor Regression Grading System for Long-Term Outcome in Patients with Locally Advanced Rectal Cancer.

BACKGROUND: The National Comprehensive Cancer Network's Rectal Cancer Guideline Panel recommends American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) system to evaluate pathologic response to neoadjuvant chemoradiotherapy for locally advanced rectal cancer (LARC). Yet, the clinical significance of the AJCC/CAP TRG system has not been fully defined. MATERIALS AND METHODS: This was a multicenter, retrospectively recruited, and prospectively maintained cohort study. Patients with LARC from one institution formed the discovery set, and cases from external independent institutions formed a validation set to verify the findings from discovery set. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were assessed by Kaplan-Meier analysis, log-rank test, and Cox regression model. RESULTS: The discovery set (940 cases) found, and the validation set (2,156 cases) further confirmed, that inferior AJCC/CAP TRG categories were closely /ccorrelated with unfavorable survival (OS, DFS, LRFS, and DMFS) and higher risk of disease progression (death, accumulative relapse, local recurrence, and distant metastasis) (all p < .05). Significantly, pairwise comparison revealed that any two of four TRG categories had the distinguished survival and risk of disease progression. After propensity score matching, AJCC/CAP TRG0 category (pathological complete response) patients treated with or without adjuvant chemotherapy displayed similar survival of OS, DFS, LRFS, and DMFS (all p > .05). For AJCC/CAP TRG1-3 cases, adjuvant chemotherapy treatment significantly improved 3-year OS (90.2% vs. 84.6%, p < .001). Multivariate analysis demonstrated the AJCC/CAP TRG system was an independent prognostic surrogate. CONCLUSION: AJCC/CAP TRG system, an accurate prognostic surrogate, appears ideal for further strategizing adjuvant chemotherapy for LARC. IMPLICATIONS FOR PRACTICE: The National Comprehensive Cancer Network recommends the American Joint Committee of Cancer and College of American Pathologists (AJCC/CAP) tumor regression grading (TRG) four-category system to evaluate the pathologic response to neoadjuvant treatment for patients with locally advanced rectal cancer; however, the clinical significance of the AJCC/CAP TRG system has not yet been clearly addressed. This study found, for the first time, that any two of four AJCC/CAP TRG categories had the distinguished long-term survival outcome. Importantly, adjuvant chemotherapy may improve the 3-year overall survival for AJCC/CAP TRG1-3 category patients but not for AJCC/CAP TRG0 category patients. Thus, AJCC/CAP TRG system, an accurate surrogate of long-term survival outcome, is useful in guiding adjuvant chemotherapy management for rectal cancer.

Predicting Adverse Outcomes for Shiga Toxin-Producing Escherichia coli Infections in Emergency Departments.

OBJECTIVE: To assess the performance of a hemolytic uremic syndrome (HUS) severity score among children with Shiga toxin-producing Escherichia coli (STEC) infections and HUS by stratifying them according to their risk of adverse events. The score has not been previously evaluated in a North American acute care setting. STUDY DESIGN: We reviewed medical records of children <18 years old infected with STEC and treated in 1 of 38 participating emergency departments in North America between 2011 and 2015. The HUS severity score (hemoglobin [g/dL] plus 2-times serum creatinine [mg/dL]) was calculated using first available laboratory results. Children with scores >13 were designated as high-risk. We assessed score performance to predict severe adverse events (ie, dialysis, neurologic complication, respiratory failure, and death) using discrimination and net benefit (ie, threshold probability), with subgroup analyses by age and day-of-illness. RESULTS: A total of 167 children had HUS, of whom 92.8% (155/167) had relevant data to calculate the score; 60.6% (94/155) experienced a severe adverse event. Discrimination was acceptable overall (area under the curve 0.71, 95% CI 0.63-0.79) and better among children <5 years old (area under the curve 0.77, 95% CI 0.68-0.87). For children <5 years, greatest net benefit was achieved for a threshold probability >26%. CONCLUSIONS: The HUS severity score was able to discriminate between high- and low-risk children <5 years old with STEC-associated HUS at a statistically acceptable level; however, it did not appear to provide clinical benefit at a meaningful risk threshold.

Diagnostic Test Accuracy of Commercial Tests for Detection of Shiga Toxin-Producing Escherichia coli: A Systematic Review and Meta-Analysis.

BACKGROUND: Rapid detection of Shiga toxin-producing Escherichia coli (STEC) enables appropriate monitoring and treatment. We synthesized available evidence to compare the performance of enzyme immunoassay (EIA) and PCR tests for the detection of STEC. METHODS: We searched published and gray literature for studies of STEC EIA and/or PCR diagnostic test accuracy relative to reference standards including at least one nucleic acid amplification test. Two reviewers independently screened studies, extracted data, and assessed quality with the second version of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool. Bivariate random effects models were used to meta-analyze the clinical sensitivity and specificity of commercial EIA and PCR STEC diagnostic tests, and summary receiver operator characteristic curves were constructed. We evaluated the certainty of evidence with the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: We identified 43 articles reflecting 25 260 specimens. Meta-analysis of EIA and PCR accuracy included 25 and 22 articles, respectively. STEC EIA pooled sensitivity and specificity were 0.681 (95% CI, 0.571-0.773; very low certainty of evidence) and 1.00 (95% CI, 0.998-1.00; moderate certainty of evidence), respectively. STEC PCR pooled sensitivity and specificity were 1.00 (95% CI, 0.904-1.00; low certainty of evidence) and 0.999 (95% CI, 0.997-0.999; low certainty of evidence), respectively. Certainty of evidence was downgraded because of high risk of bias. CONCLUSIONS: PCR tests to identify the presence of STEC are more sensitive than EIA tests, with no meaningful loss of specificity. However, given the low certainty of evidence, our results may overestimate the difference in performance.

Association Between Traditional Herbal Diet and Nasopharyngeal Carcinoma Risk: A Prospective Cohort Study in Southern China.

INTRODUCTION: Prospective evidence for herbal diet and nasopharyngeal carcinoma (NPC) development is absent. We therefore evaluated the associations of herbal soup and herbal tea with NPC in a prospective cohort study in southern China. METHODS: Based on an NPC screening cohort established in 2008-2015, information on herbal diet consumption, potential confounding factors, and Epstein-Barr virus (EBV) antibody levels were collected from 10,179 individuals aged 30-69 years in Sihui city, southern China. Cox regression models were performed to examine herbal diet with NPC risk, and logistic regression models were used to examine herbal diet with EBV reactivation. RESULTS: During a median of 7.54 years of follow-up, 69 participants developed NPC. Herbal soup consumption was associated with decreased NPC risk, with HRs of 0.31 (95% confidence interval (CI): 0.15-0.62) for the highest intake frequency and 0.29 (95% CI: 0.16-0.51) for a longer duration. However, herbal tea was not significantly associated. Moreover, we identified herbal soup was inversely associated with EBV seropositivity among all the participants at baseline, with the adjusted ORs being 0.78 (95% CI: 0.65-0.93) for immunoglobulin A antibodies against EBV capsid antigens (VCA-IgA) and 0.76 (95% CI: 0.64-0.91) for nuclear antigen 1 (EBNA1-IgA) in those with the highest frequency and 0.70 (95% CI: 0.59-0.84) for VCA-IgA and 0.64 (95% CI: 0.54-0.77) for EBNA1-IgA in those with the longer duration. Inverse associations were also observed in non-NPC individuals. CONCLUSIONS: With inhibition of EBV reactivation by plants, herbal soup could significantly decrease the risk of NPC in endemic areas.

Community engagement approaches for Indigenous health research: recommendations based on an integrative review.

OBJECTIVE: Community engagement practices in Indigenous health research are promoted as a means of decolonising research, but there is no comprehensive synthesis of approaches in the literature. Our aim was to assemble and qualitatively synthesise a comprehensive list of actionable recommendations to enhance community engagement practices with Indigenous peoples in Canada, the USA, Australia and New Zealand. DESIGN: Integrative review of the literature in medical (Medline, Cumulative Index to Nursing and Allied Health Literature and Embase) and Google and WHO databases (search cut-off date 21 July 2020). ARTICLE SELECTION: Studies that contained details regarding Indigenous community engagement frameworks, principles or practices in the field of health were included, with exclusion of non-English publications. Two reviewers independently screened the articles in duplicate and reviewed full-text articles. ANALYSIS: Recommendations for community engagement approaches were extracted and thematically synthesised through content analysis. RESULTS: A total of 63 studies were included in the review, with 1345 individual recommendations extracted. These were synthesised into a list of 37 recommendations for community engagement approaches in Indigenous health research, categorised by stage of research. In addition, activities applicable to all phases of research were identified: partnership and trust building and active reflection. CONCLUSIONS: We provide a comprehensive list of recommendations for Indigenous community engagement approaches in health research. A limitation of this review is that it may not address all aspects applicable to specific Indigenous community settings and contexts. We encourage anyone who does research with Indigenous communities to reflect on their practices, encouraging changes in research processes that are strengths based.

Characterization of indigenous community engagement in arthritis studies conducted in Canada, United States of America, Australia and New Zealand.

BACKGROUND: Research adhering to community engagement processes leads to improved outcomes. The level of Indigenous communities' engagement in rheumatology research is unknown. OBJECTIVE: To characterize the frequency and level of community engagement reporting in arthritis studies conducted in Australia (AUS), Canada (CAN), New Zealand (NZ) and the United States of America (USA). METHODS: Studies identified through systematic reviews on topics of arthritis epidemiology, disease phenotypes and outcomes, health service utilization and mortality in Indigenous populations of AUS, CAN, NZ and USA, were evaluated for their descriptions of community engagement. The level of community engagement during inception, data collection and results interpretation/dissemination stages of research was evaluated using a custom-made instrument, which ranked studies along the community engagement spectrum (i.e. inform-consult-involve-collaborate-empower). Meaningful community engagement was defined as involving, collaborating or empowering communities. Descriptive analyses for community engagement were performed and secondary non-parametric inferential analyses were conducted to evaluate the possible associations between year of publication, origin of the research idea, publication type and region of study; and meaningful community engagement. RESULTS: Only 34% (n = 69) of the 205 studies identified reported community engagement at ≥ 1 stage of research. Nearly all studies that engaged communities (99% (n = 68)) did so during data collection, while only 10% (n = 7) did so at the inception of research and 16% (n = 11) described community engagement at the results' interpretation/dissemination stage. Most studies provided community engagement descriptions that were assessed to be at the lower end of the spectrum. At the inception of research stage, 3 studies reported consulting communities, while 42 studies reported community consultation at data collection stage and 4 studies reported informing or consulting communities at the interpretation/dissemination of results stage. Only 4 studies described meaningful community engagement through all stages of the research. Inferential statistics identified that studies with research ideas that originated from the Indigenous communities involved were significantly more associated with achieving meaningful community engagement. CONCLUSIONS: The reporting of Indigenous community engagement in published arthritis studies is limited in frequency and is most frequently described at the lower end of the community engagement spectrum. Processes that support meaningful community engagement are to be promoted.

Smoking can increase nasopharyngeal carcinoma risk by repeatedly reactivating Epstein-Barr Virus: An analysis of a prospective study in southern China.

BACKGROUND: The association between smoking and nasopharyngeal carcinoma (NPC) is still uncertain. The aim of this study was to validate smoking effect on NPC and explore if smoking can induce NPC by persistently reactivating EBV in long-term based on a prospective cohort design. METHODS: A NPC screening cohort with 10 181 eligible residents in Sihui city, southern China was conducted from 2008 to 2015. The smoking habit was investigated through the trained interviewers and EBV antibodies (VCA-IgA, EBNA1-IgA) as screening markers were tested periodically. New NPC cases were identified through local cancer registry. Cox's regression model was used to estimate the adjusted hazard ratios (aHRs) of smoking on NPC incidence. In the non-NPC participants, the associations between smoking and EBV seropositivity in different periods were assessed by logistic regression and generalized estimating equations (GEE). RESULTS: With a median of 7.54 years, 71 NPCs were diagnosed ≥1 year after recruitment. Compared with never smokers, the aHRs of developing NPC among ever smokers were 3.00 (95%CI: 1.46-6.16). Stratified by sex, the HRs of ever smoking were 2.59 (95%CI: 1.07-6.23) for male and 3.75 (95%CI: 1.25-11.20) for female, respectively. Among the non-NPC individuals, ever smoking was not only associated with EBV seropositivity at baseline, but also in the 3-5 years of follow up, with adjusted odds ratios (aORs) of 1.68 (95%CI: 1.29-2.18) for VCA-IgA and 1.92 (95%CI: 1.42-2.59) for EBNA1-IgA. Among the smokers who were tested EBV antibodies at least twice, the similar results were obtained using GEE. CONCLUSION: Smoking could significantly increase the long-term risk of NPC in southern China, partly by persistently reactivating EBV.

Performance of commercial tests for molecular detection of Shiga toxin-producing Escherichia coli (STEC): a systematic review and meta-analysis protocol.

INTRODUCTION: Rapid detection of Shiga toxin-producing Escherichia coli (STEC) enables appropriate treatment. Numerous commercially available molecular tests exist, but they vary in clinical performance. This systematic review aims to synthesise available evidence to compare the clinical performance of enzyme immunoassay (EIA) and nucleic acid amplification tests (NAATs) for the detection of STEC. METHODS AND ANALYSIS: The following databases will be searched employing a standardised search strategy: Medline, Embase, Cochrane CENTRAL Register of Controlled Trials, Cochrane Database of Systematic Reviews, PubMed, Scopus and Web of Science. Grey literature will be searched under advice from a medical librarian. Independent reviewers will screen titles, abstracts and full texts of retrieved studies for relevant studies. Data will be extracted independently by two reviewers, using a piloted template. Quality Assessment of Diagnostic Accuracy Studies-2 will be employed to assess the risk of bias of individual studies, and the quality of evidence will be assessed with the Grading of Recommendations Assessment, Development and Evaluation approach. A bivariate random-effects model will be used to meta-analyse the sensitivity and specificity of commercial STEC diagnostic tests, and a hierarchical summary receiver operator characteristic curve will be constructed. Studies of single test accuracy of EIA and NAATs and studies of comparative accuracy will be analysed separately. ETHICS AND DISSEMINATION: Ethics approval was not required for this systematic review and meta-analysis. Findings will be disseminated in conferences, through a peer-reviewed journal and via personal interactions with relevant stakeholders. PROSPERO REGISTRATION NUMBER: CRD42018099119.

Decreased macrophage inflammatory protein (MIP)-1α and MIP-1ß increase the risk of developing nasopharyngeal carcinoma.

BACKGROUND: The association of circulating inflammation markers with nasopharyngeal carcinoma (NPC) is still largely unclear. This study aimed to comprehensively explore the relationship between circulating cytokine levels and the subsequent risk of NPC with a two-stage epidemiologic study in southern China. METHODS: The serum levels of 33 inflammatory cytokines were first measured in a hospital-based case-control study (150 NPC patients and 150 controls) using multiplex assay platforms. Marker levels were categorized into two or more groups based on the proportion of sample measurements that was above the lower limit of detection. Odds ratios (ORs) and 95% confidence intervals (CIs) relating the serum marker concentration to the risk of NPC were computed by multivariable logistic regression models. The associations were validated in 60 patients with NPC and 120 controls in a subsequent nested case-control study within a NPC screening trial. Potential interactions between serum cytokines and Epstein-Barr virus (EBV) relating to the risk of NPC were assessed using a likelihood ratio test. RESULTS: The levels of serum macrophage inflammatory protein (MIP)-1α and MIP-1ß in the highest categories were associated with a decreased risk of NPC in both the case-control study (MIP-1α: OR = 0.49, 95% CI = 0.26-0.95; MIP-1ß: OR = 0.47, 95% CI = 0.22-1.00) and the nested case-control study (MIP-1α: OR = 0.13, 95% CI = 0.03-0.62; MIP-1ß: OR = 0.20, 95% CI = 0.04-0.94), compared with those in the lowest categories. Furthermore, individuals with lower levels of these two cytokine markers who were EBV seropositive presented with a largely higher risk of NPC compared with patients with higher levels who were EBV seronegative in both the case-control study (MIP-1α: OR = 16.28, 95% CI = 7.11-37.23; MIP-1ß: OR = 12.86, 95% CI = 5.9-28.05) and the nested case-control study (MIP-1α: OR = 86.12, 95% CI = 10.58-701.03; MIP-1ß: OR = 115.44, 95% CI = 13.92-957.73). CONCLUSIONS: Decreased preclinical MIP-1α and MIP-1ß levels might be associated with a subsequently increased risk of NPC. More mechanistic studies are required to fully understand this finding.

Evaluation of seven recombinant VCA-IgA ELISA kits for the diagnosis of nasopharyngeal carcinoma in China: a case-control trial.

OBJECTIVE: Seven recombinant viral capsid antigen-IgA (VCA-IgA) ELISA kits are widely used in China, but their diagnostic effects have not been evaluated. In this study, we evaluated whether the diagnostic effects of these kits are similar to those of the standard kit (EUROIMMUN, Lübeck, Germany). METHODS: A diagnostic case-control trial was conducted with 200 cases of nasopharyngeal carcinoma (NPC) and 200 controls from NPC-endemic areas in southern China. The areas under the curve (AUCs), the sensitivities and the specificities of testing kits were compared with those of the standard kit. The test-retest reliability of each kit was determined by intraclass correlation coefficient (ICC). Their diagnostic accuracy in combination with Epstein-Barr virus nuclear antigen 1-IgA (EBNA1-IgA) was also evaluated in logistic models. RESULTS: Three testing kits-BB, HA and KSB-showed diagnostic accuracy equal to that of the standard kit, with good performance in the AUCs (0.926-0.945), and no significant differences in sensitivity were found between early-stage and advanced-stage NPCs. ICCs exceeded 0.8. Three logistic regression models were built, and the AUCs of these models (0.961-0.977) were better than those of the individual VCA-IgA kits. All new models had diagnostic accuracy equal to that of the standard kit. New cut-off values of these three kits and their corresponding combinations for researchers to replicate and use in NPC early detection and screening in the future were provided. CONCLUSIONS: Three recombinant VCA-IgA kits-BB,HA and KSB-had diagnostic effects equal to those of the standard kit, and, in combination with EBNA1-IgA in logistic regression models, can be used in future screening for NPC.